Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis.

Yasuyuki Mizutani ,Shinji Mii ,Yukihiro Shiraki ,Tadashi Iida ,Hiroki Kobayashi ,Akitoshi Hara ,Tsutomu Fujii ,Liang Weng ,Susan L Woods ,Makoto Matsuyama ,Daniel L Worthley ,Teppei Shimamura ,Tomoe Kobayashi ,Mitsuhiro Fujishiro ,Takaki Miyata ,Naoya Asai ,Suguru Yamada ,Yoshiki Hirooka ,Junpei Yamaguchi ,Tongtong Wang ,Nobutoshi Esaki ,Kazunori Ando ,Kaori Ushida ,Seiichiro Ishihara ,Atsushi Masamune ,Atsushi Enomoto ,Suzanne M Ponik ,Matthew W Conklin ,Arata Nagasaka ,Hisashi Haga ,Masahide Takahashi

doi:10.1158/0008-5472.can-19-0454

Abstract

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression. SIGNIFICANCE: Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5367/F1.large.jpg.

Highlights

Tumors are not a homogenous mass of cancer cells, and comprise many types of noncancer cells, including cancerassociated fibroblasts (CAF), myeloid cells, and lymphocytes [1, 2]
Meflin was expressed by pancreatic stellate cells (PSC) isolated from the pancreas, which were positive for desmin but not for epithelial or endothelial markers, as indicated by Western blot analysis (Fig. 1D)
Meflin marks a population of CAFs in pancreatic ductal adenocarcinoma (PDAC), with high Meflin expression correlating with favorable outcome in patients with PDAC and a PDAC mouse model

Summary

Introduction

Tumors are not a homogenous mass of cancer cells, and comprise many types of noncancer cells, including cancerassociated fibroblasts (CAF), myeloid cells, and lymphocytes [1, 2]. These cells, together with tumor vessels and the extracellular matrix (ECM), shape the tumor microenvironment (TME), which is vital for the development and progression of cancer and tumor immunity and resistance to anticancer therapies [1, 2]. CAFs constitute a major component of the TME and produce various types of ECM proteins, such as collagen, and soluble signaling molecules [3,4,5,6,7,8]. Clinical trials of therapeutics that target CAFs are emerging, with investigations on the underlying mechanisms [4, 8, 19, 20]

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Results

Conclusion